The present invention relates to various pyranoindazoles. These novel compounds are useful for lowering and controlling normal or elevated intraocular pressure (IOP) and for treating glaucoma.
The disease state referred to as glaucoma is characterized by a permanent loss of visual function due to irreversible damage to the optic nerve. The several morphologically or functionally distinct types of glaucoma are typically characterized by elevated IOP, which is considered to be causally related to the pathological course of the disease. Ocular hypertension is a condition wherein intraocular pressure is elevated but no apparent loss of visual function has occurred; such patients are considered to be at high risk for the eventual development of the visual loss associated with glaucoma. If glaucoma or ocular hypertension is detected early and treated promptly with medications that effectively reduce elevated intraocular pressure, loss of visual function or its progressive deterioration can generally be ameliorated. Drug therapies that have proven to be effective for the reduction of intraocular pressure include both agents that decrease aqueous humor production and agents that increase the outflow facility. Such therapies are in general administered by one of two possible routes, topically (direct application to the eye) or orally.
There are some individuals who do not respond well when treated with certain existing glaucoma therapies. There is, therefore, a need for other topical therapeutic agents that control IOP.
Serotonergic 5-HT1A agonists have been reported as being neuroprotective in animal models and many of these agents have been evaluated for the treatment of acute stroke among other indications. This class of compounds has been mentioned for the treatment of glaucoma (lowering and controlling IOP), see e.g., WO 98/18458 (DeSantis, et al.) and EP 0771563A2 (Mano, et al.). Osborne, et al. (Ophthalmologica, Vol. 210:308-314, 1996) teach that 8-hydroxydipropylaminotetralin (8-OH-DPAT) (a 5-HT1A agonist) reduces IOP in rabbits. Wang, et al. (Current Eye Research, Vol. 16(8):769-775, August 1997, and IVOS, Vol. 39(4), S488, March, 1998) indicate that 5-methylurapidil, an xcex11A antagonist and 5-HT1A agonist lowers IOP in the monkey, but due to its xcex11A receptor activity. Also, 5-HT1A antagonists are disclosed as being useful for the treatment of glaucoma (elevated IOP) (e.g., WO 92/0338, McLees). Furthermore, DeSai, et al. (WO 97/35579) and Macor, et al. (U.S. Pat. No. 5,578,612) relate to the use of 5-HT1 and 5-HT-1-like agonists for the treatment of glaucoma (elevated IOP). These anti-migraine compounds, e.g., sumatriptan and naratriptan and related compounds, are 5-HT1B,D,E,F agonists.
It has been found that serotonergic compounds which possess agonist activity at 5-HT2 receptors effectively lower and control normal and elevated IOP and are useful for treating glaucoma, see commonly owned co-pending application, PCT/US99/19888, incorporated in its entirety by reference herein. Compounds that act as agonists at 5-HT2 receptors are well known and have shown a variety of utilities, primarily for disorders or conditions associated with the central nervous system (CNS). U.S. Pat. No. 5,494,928 relates to certain 2-(indol-1-yl)-ethylamine derivatives that are 5-HT2c agonists for the treatment of obsessive compulsive disorder and other CNS derived personality disorders. U.S. Pat. No. 5,571,833 relates to tryptamine derivatives that are 5-HT2 agonists for the treatment of portal hypertension and migraine. U.S. Pat. No. 5,874,477 relates to a method for treating malaria using 5-HT2A/2C agonists. U.S. Pat. No. 5,902,815 relates to the use of 5-HT2A agonists to prevent adverse effects of NMDA receptor hypo-function. WO 98/31354 relates to 5-HT2B agonists for the treatment of depression and other CNS conditions. WO 00/12475 relates to indoline derivatives and WO 00/12510 and WO 00/44753 relate to certain indole derivatives as 5-HT2B and 5-HT2C receptor agonists for the treatment of a variety of disorders of the central nervous system, but especially for the treatment of obesity. WO 00/35922 relates to certain pyrazino[1,2-a]quinoxaline derivates as 5-HT2C agonists for the treatment of obsessive compulsive disorder, depression, eating disorders, and other disorders involving the CNS. WO 00/77002 and WO 00/77010 relate to certain substituted tetracyclic pyrido[4,3-b]indoles as 5-HT2C agonists with utility for the treatment of central nervous system disorders including obesity, anxiety, depression, sleep is disorders, cephalic pain, and social phobias among others. Agonist response at the 5-HT2A receptor is reported to be the primary activity responsible for hallucinogenic activity, with some lesser involvement of the 5-HT2C receptor possible [Psychopharmacology, Vol. 121:357, 1995].
Few furan or pyran containing fused indazoles have been reported. The chemical synthesis of 7-methyl- and 1,7-dimethyl-1H-furo[2,3-g]indazole [Gazz. Chim Ital. 106, 1083 (1976)] as well as that of 3-methyl- and 1-(4-aminophenyl)-3-methyl-1H-benzo[b]furo[2,3-g]indazole [An. Asoc. Quim. Argent. 59, 69 (1971)] has been reported without discussion of their utility. European Patent Application EP 990,650 (Intnl. Publication Number WO 98/56768) relates to substituted 2-(furo[2,3-g]indazol-1-yl)-ethylamines, such as (S)-2-(furo[2,3-g]indazol-1-yl)-1-methylethylamine, which are reported to have high selectivity and affinity for 5-HT2C receptors and are potentially useful for treating a variety of central nervous system disorders. The chemical synthesis of 9-methyl-1H-pyrano[2,3-g]indazol-7-one and the corresponding non-methylated compound was reported [Indian J. Chem. 26B, 436 (1987)] with no mention of utility.
U.S. Pat. Nos. 5,561,150 and 5,646,173 relate to certain tricyclic pyrazole derivative compounds which are identified as being 5-HT2C agonists for the treatment of CNS diseases and are primarily directed to lipophilic analogs that have a high probability of entering the brain. Similarly, WO 98/56768 relates to tricyclic 5-HT2C agonists for the treatment of CNS diseases. All the patents and publications mentioned above and throughout are incorporated in their entirety by reference herein.
5-Hyroxytryptamine (serotonin) does not cross the blood-brain barrier and enter the brain. However, in order to increase brain serotonin levels the administration of 5-hydroxy-tryptophan can be employed. The transport of 5-hydroxy-tryptophan into the brain readily occurs, and once in the brain 5-hydroxy-tryptophan is rapidly decarboxylated to provide serotonin.
Accordingly, there is a need to provide new compounds which avoid the disadvantages described above and which provide increased chemical stability and a desired length of therapeutic activity, for instance, in decreasing intraocular pressure and treating glaucoma.
A feature of the present invention is to provide novel compounds which are 5-HT2 agonists.
Another feature of the present invention is to provide compounds which have increased chemical stability and which are useful in lowering and controlling normal or elevated intraocular pressure and/or treating glaucoma.
Another feature of the present invention is to provide compounds which provide a desired level of therapeutic activity in lowering and controlling normal or elevated intraocular pressure and/or treating glaucoma.
Additional features and advantages of the present invention will be set forth in part in the description that follows, and in part will be apparent from the description, or may be learned by practice of the present invention. The objectives and other advantages of the present invention will be realized and attained by means of the elements and combinations particularly pointed out in the description and appended claims.
To achieve these and other advantages, and in accordance with the purposes of the present invention, as embodied and broadly described herein, the present invention relates to a compound having the Formula I: 
or pharmaceutically acceptable salts or solvates or prodrug forms of the compounds of Formula I. In the formula, R1 and R2 are independently chosen from hydrogen or an alkyl group, such as C1-4 alkyl;
R3 and R4 are independently chosen from hydrogen or an alkyl group, such as C1-4 alkyl or;
R3 and R4 and the carbon atom to which they are attached can form a cycloalkyl ring, or furthermore,
R2 and R3 together can be (CH2)m to form a saturated heterocycle;
R5 is chosen from hydrogen, halogen, an alkyl group, such as C1-6 alkyl or C1-4 alkyl substituted by halogen;
R6 and R7 are independently chosen from hydrogen, halogen, cyano, an alkylthio such as C1-4 alkylthio, an alkyl such as C1-4 alkyl, or a substituted alkyl such as C1-4 alkyl substituted by halogen;
R8 and R9 are independently chosen from hydrogen, hydroxyl, an alkyl such as C1-6 alkyl, an alkoxy such as C1-6alkoxy, xe2x95x90O, NR10R11, OC(xe2x95x90O)NR1R2, OC(xe2x95x90O)C1-4alkyl, an alkylthiol such as C1-6 alkylthiol, a substituted alkyl such as C1-6 alkyl substituted with halogen, or NR10R11, OR12, CO2R13, or CONR14R15, and further R8 and R9 can be chosen from Z-(CH2)mxe2x80x94NR10R11, Z-(CH2)mxe2x80x94OR12, Z-(CH2)Pxe2x80x94C(xe2x95x90O)OR13 or Z-(CH2)Pxe2x80x94C(xe2x95x90O)NR14R15;
R10 and R11 are independently chosen from hydrogen, an alkyl group such as C1-4 alkyl, C(xe2x95x90O)C1-4 alkyl, C(xe2x95x90O)OC1-4 alkyl, C(xe2x95x90O)NR1R2, or a substituted alkyl such as C1-6 alkyl substituted with halogen, hydroxyl, NR1R2 or R10 and R11 together can complete a saturated 5 or 6-membered heterocyclic ring, which can include an additional heteroatom selected from N, O, or S when a 6-membered ring;
R12 is hydrogen, C1-6alkyl, C(xe2x95x90O)C1-6alkyl, or C(xe2x95x90O)C1-6alkyl substituted by hydroxyl, C1-4alkoxide, or halide;
R13 is hydrogen, C1-6alkyl, C1-6alkyl substituted by hydroxyl, C1-4alkoxy, or halide;
R14 and R15 are independently chosen from hydrogen, hydroxyl, C1-4alkoxy, C1-6alkyl, C2-6alkyl substituted by hydroxyl, C1-4alkoxy, halide, or R14 and R15 can be combined to form a saturated heterocyclic ring selected from pyrrolidine, piperidine, piperazine, or morpholine;
A is (CH2)n, Cxe2x95x90O, or CHC1-4alkyl;
B is either a single or a double bond, wherein when B is a double bond, R8 and R9 are selected from hydrogen, an alkyl group, such as C1-4alkyl, or a substituted alkyl group, such as a C1-4alkyl substituted by halogen, hydroxyl, or NR10R11;
when A is (CH2)n and n is 0, R8 is chosen from CO2R13, C1-6alkyl substituted with OR12, NR10R11, CO2R13 or CONR14R15 and R9 is selected from hydrogen or C1-2alkyl and B is a single bond;
Z is O or S(O)n;
m=2-4;
n=0-2;
p=1-2;
X and Y are either N or C, wherein X and Y are different from each other; and the dashed bonds denote a suitably appointed single and double bond.
In another preferred embodiment of the formula, R1 and R2 are independently chosen from hydrogen or an alkyl group, such as C1-4 alkyl;
R3 and R4 are independently chosen from hydrogen or an alkyl group, such as C1-4 alkyl or;
R3 and R4 and the carbon atom to which they are attached can form a cycloalkyl ring (e.g., cyclopropyl ring), or furthermore,
R2 and R3 together can be (CH2)m to form a saturated heterocycle;
R5 is chosen from hydrogen, halogen, a substituted or unsubstituted alkyl group, such as C1-16 alkyl or C1-4alkyl substituted by halogen;
R6 and R7 are independently chosen from hydrogen, halogen, cyano, an alkylthio such as C1-4 alkylthio, an alkyl such as C1-4 alkyl, or a substituted alkyl such as C1-4 alkyl substituted by halogen;
R8 and R9 are independently chosen from hydrogen, hydroxyl, an alkyl such as C1-6 alkyl, an alkoxy such as C1-6 alkoxy, xe2x95x90O, NR10R11, OC(xe2x95x90O)NR1R2, OC(xe2x95x90O)C1-4alkyl, an alkylthiol such as C1-6 alkylthiol, a substituted alkyl such as C1-6 alkyl substituted with halogen, NR10R11, OR12, CO2R13, or CONR14R15, and further R8 and R9 can be chosen from Z-(CH2)mxe2x80x94OR12, Z-(CH2)Pxe2x80x94C(xe2x95x90O)OR13, or Z-(CH2)Pxe2x80x94NR14R15;
R10 and R11 are independently chosen from hydrogen, an alkyl group such as C1-4 alkyl, C(xe2x95x90O)C1-4 alkyl, C(xe2x95x90O)OC1-4 alkyl, C(xe2x95x90O)NR1R2, or a substituted alkyl group such as C1-6 alkyl substituted with halogen, hydroxyl, or NR1R2, or R10 and R11 together can complete a saturated 5 or 6-membered heterocyclic ring, which can include an additional heteroatom selected from N, O, or S when a 6-membered ring;
R12 is C1-6alkyl, C(xe2x95x90O)C1-6alkyl, or C(xe2x95x90O)C1-6alkyl substituted by hydroxyl, C1-4alkoxide, or halide;
R13 is hydrogen, C1-6alkyl, C1-6alkyl substituted by hydroxyl, C1-4alkoxy, or halide;
R14 and R15 are independently chosen from hydrogen, hydroxyl, C1-4alkoxy, C1-6alkyl, is C1-6alkyl substituted by hydroxyl, C1-4alkoxy, halide, or R14 and R15 can be combined to form a saturated heterocyclic ring selected from pyrrolidine, piperidine, piperazine, or morpholine;
A is (CH2)n, Cxe2x95x90O, or CHC1-4alkyl;
B is either a single or a double bond, wherein when B is a double bond, R8 and R9 are selected from hydrogen, an alkyl group, such as C1-4alkyl, or a substituted alkyl group, such as a C1-4alkyl substituted by halogen, hydroxyl, or NR10R11;
when A is (CH2)n and n is 0, R8 is chosen from C1-2alkyl substituted by hydroxyl or OR12 and R9 is selected from hydrogen or C1-2alkyl and B is a single bond;
X and Y are either N or C, wherein X and Y are different from each other; and the dashed bonds denote a suitably appointed single and double bond.
Z is O or S(O)n;
m=2-4;
n=0-2; and
p=1-2.
The present invention further relates to pharmaceutical compositions containing at least one compound of Formula I.
The present invention further relates to methods to lower and/or control normal or elevated intraocular pressure by administering an effective amount of a composition containing a compound having Formula I as described above.
The present invention also relates to a method for treating glaucoma which involves administering an effective amount of a composition containing a compound having Formula I as described above.
It is to be understood that both the foregoing general description and the following detailed description are exemplary and explanatory only and are intended to provide a further explanation of the present invention, as claimed.
The present invention relates to a variety of compounds which are useful according to the present invention. These compounds are generally represented by the following Formula I. 
In the formula, R1 and R2 are independently chosen from hydrogen or an alkyl group, such as C1-4 alkyl;
R3 and R4 are independently chosen from hydrogen or an alkyl group, such as C1-4 alkyl or;
R3 and R4 and the carbon atom to which they are attached can form a cycloalkyl ring (e.g., cyclopropyl ring), or furthermore,
R2 and R3 together can be (CH2)m to form a saturated heterocycle;
R5 is chosen from hydrogen, halogen, a substituted or unsubstituted alkyl group, such as C1-6 alkyl or C1-4 alkyl substituted by halogen;
R6 and R7 are independently chosen from hydrogen, halogen, cyano, an alkylthio such as C1-4 alkylthio, an alkyl such as C1-4 alkyl, or a substituted alkyl such as C1-4 alkyl substituted by halogen;
R8 and R9 are independently chosen from hydrogen, hydroxyl, an alkyl such as C1-6 alkyl, an alkoxy such as C1-6 alkoxy, xe2x95x90O, NR10R11, OC(xe2x95x90O)NR1R2, OC(xe2x95x90O)C4alkyl, an alkylthiol such as C1-6 alkylthiol, a substituted alkyl such as C1-6 alkyl substituted with halogen, or NR10R11, OR2, CO2R13, or CONR14R15, and further R8 and R9 can be chosen from Z-(CH2)mxe2x80x94NR10R11, Z-(CH2)mxe2x80x94OR12, Z-(CH2)Pxe2x80x94C(xe2x95x90O)OR13, or Z-(CH2)Pxe2x80x94C(xe2x95x90O)NR14R15;
R10 and R11 are independently chosen from hydrogen, an alkyl group such as C1-4 alkyl, C(xe2x95x90O)C1-4 alkyl, C(xe2x95x90O)OC1-4 alkyl, C(xe2x95x90O)NR1R2, or a substituted alkyl group such as C1-6 alkyl substituted with halogen, hydroxyl, or NR1R2, or R10 and R11 together can complete a saturated 5 or 6-membered heterocyclic ring, which can include an additional heteroatom selected from N, O, or S when a 6-membered ring;
R12 is hydrogen, C1-6alkyl, C(xe2x95x90O)C1-6alkyl, or C(xe2x95x90O)C1-6alkyl substituted by hydroxyl, C1-4alkoxide, or halide;
R13 is hydrogen, C1-6alkyl, C1-6alkyl substituted by hydroxyl, C1-4alkoxy, or halide;
R14 and R15 are independently chosen from hydrogen, hydroxyl, C1-4alkoxy, C1-6alkyl, C2,alkyl substituted by hydroxyl, C1-4alkoxy, halide, or R14 and R15 can be combined to form a saturated heterocyclic ring selected from pyrrolidine, piperidine, piperazine, or morpholine;
A is (CH2)n, Cxe2x95x90O, or CHC1-4alkyl;
B is either a single or a double bond, wherein when B is a double bond, R8 and R9 are selected from hydrogen, an alkyl group, such as C1-4alkyl, or a substituted alkyl group, such as a C1-4alkyl substituted by halogen, hydroxyl, or NR10R11;
when A is (CH2)n and n is 0, R8 is chosen from CO2R13, C1-6alkyl substituted with OR12, NR10R11, CO2R13 or CONR14R15 and R9 is selected from hydrogen or C1-2alkyl and B is a single bond;
Z is O or S(O)n;
m=2-4;
n=0-2;
p=1-2;
X and Y are either N or C, wherein X and Y are different from each other; and the dashed bonds denote a suitably appointed single and double bond.
In another preferred embodiment of Formula 1, R1 and R2 are independently chosen from hydrogen or an alkyl group, such as C1-4 alkyl;
R3 and R4 are independently chosen from hydrogen or an alkyl group, such as C1-4 alkyl or;
R3 and R4 and the carbon atom to which they are attached can form a cycloalkyl ring (e.g., cyclopropyl ring), or furthermore,
R2 and R3 together can be (CH2)m to form a saturated heterocycle;
R5 is chosen from hydrogen, halogen, a substituted or unsubstituted alkyl group, such as C1-6 alkyl or C1-4 alkyl substituted by halogen;
R6 and R7 are independently chosen from hydrogen, halogen, cyano, an alkylthio such as C1-4 alkylthio, an alkyl such as C1-4 alkyl, or a substituted alkyl such as C1-4 alkyl substituted by halogen;
R8 and R9 are independently chosen from hydrogen, hydroxyl, an alkyl such as C1-6 alkyl, an alkoxy such as C1-6 alkoxy, xe2x95x90O, NR10R11, OC(xe2x95x90O)NR1R2, OC(xe2x95x90O)C1-4alkyl, an alkylthiol such as C1-6 alkylthiol, a substituted alkyl such as C1-6 alkyl substituted with halogen, NR10R11, OR12, CO2R13, or CONR14R15, and further R8 and R9 can be chosen from Z-(CH2)mxe2x80x94OR12, Z-(CH2)Pxe2x80x94C(xe2x95x90O)OR13 or Z-(CH2)Pxe2x80x94NR14R15;
R10 and R11 are independently chosen from hydrogen, an alkyl group such as C1-4 alkyl, C(xe2x95x90O)C1-4 alkyl, C(xe2x95x90O)OC1-4 alkyl, C(xe2x95x90O)NR1R2, or a substituted alkyl group such as C1-6 alkyl substituted with halogen, hydroxyl, or NR1R2, or R10 and R11 together can complete a saturated 5 or 6-membered heterocyclic ring, which can include an additional heteroatom selected from N, O, or S when a 6-membered ring;
R12 is C1-6alkyl, C(xe2x95x90O)C1-6alkyl, or C(xe2x95x90O)C1-6alkyl substituted by hydroxyl, C1-4alkoxide, or halide;
R13 is hydrogen, C1-6alkyl, C1-6alkyl substituted by hydroxyl, C1-4alkoxy, or halide;
R14 and R15 are independently chosen from hydrogen, hydroxyl, C4alkoxy, C1-6alkyl, C1-6alkyl substituted by hydroxyl, C1-4alkoxy, halide, or R14 and R15 can be combined to form a saturated heterocyclic ring selected from pyrrolidine, piperidine, piperazine, or morpholine;
A is (CH2)n, Cxe2x95x90O, or CHC1-4alkyl;
B is either a single or a double bond, wherein when B is a double bond, R8 and R9 are selected from hydrogen, an alkyl group, such as C1-4alkyl, or a substituted alkyl group, such as a C1-4alkyl substituted by halogen, hydroxyl, or NR10R11;
when A is (CH2)n and n is 0, R8 is chosen from C1-2alkyl substituted by hydroxyl or OR12 and R9 is selected from hydrogen or C1-2alkyl and B is a single bond;
X and Y are either N or C, wherein X and Y are different from each other; and the dashed bonds denote a suitably appointed single and double bond;
Z is O or S(O)n;
m=2-4;
n=0-2; and
p=1-2.
Pharmaceutically acceptable salts and solvates, and prodrug forms of the compounds of Formula I are also part of the present invention.
Preferred compounds are:
Wherein R1 and R2 are independently chosen from hydrogen or C1-4alkyl;
R3 and R4 are independently chosen from hydrogen, C1-4alkyl, or R2 and R3 together can be (CH2)m to form a saturated heterocycle;
R5 is chosen from hydrogen, halogen, or C1-6alkyl;
R6 and R7 are independently chosen from hydrogen, halogen, cyano, C1-4alkylthio, C1-4alkyl, or C1-4alkyl substituted by halogen;
R8 and R9 are chosen from hydrogen, hydroxyl, C1-6alkyl, C1-6alkoxy, NR10R11, or C1-6alkyl substituted with halogen, hydroxyl, or NR10R11;
R10 and R11 are independently chosen from hydrogen, C1-4alkyl, C(xe2x95x90O)C1-4alkyl, C(xe2x95x90O)OC1-4 alkyl, C(xe2x95x90O)NR1R2, or R10 and R11 together can complete a saturated 6-membered heterocyclic ring, which can include an additional heteroatom selected from N,
O, or S;
A is (CH2)n or CHC1-4alkyl;
B is either a single or double bond, wherein when B is a double bond, R8 and R9 are selected from hydrogen, C1-4alkyl, or C1-4alkyl substituted by halogen, hydroxy, or NR10R11;
m=3-4;
n=1-2;
X and Y are either N or C, wherein X and Y are different; and
the dashed bonds denote a suitably appointed single and double bond;
Most preferred compounds are:
Wherein R1 and R2 are independently chosen from hydrogen or C1-4alkyl;
R3 is C1-2alkyl, or R2 and R3 together can be (CH2)3 to form pyrrolidine;
R4 is hydrogen;
R5 is chosen from hydrogen or C1-6alkyl;
R6 and R7 are independently chosen from hydrogen, halogen, or C1-4alkyl;
R8 and R9 are independently chosen from hydrogen, hydroxyl, C1-6alkoxy, NR10R11, or C1-6alkyl substituted with hydroxyl or NR10R11;
R10 and R11 are independently chosen from hydrogen, C1-4alkyl, C(xe2x95x90O)C1-4alkyl, or R10 and R11 together can complete a saturated 6-membered heterocyclic ring, which can include an additional heteroatom selected from N, O, or S;
A is (CH2)n;
B is a single bond;
n=1;
X is C and Y is N; and
the dashed bonds denote a suitably appointed single and double bond.
Representative Examples of Preferred Compounds of Formula I are:
1-(2-Aminopropyl)-1,7,8,9-tetrahydro-pyrano[2,3-g]indazol-8-ol;
1-((S)-2-Aminopropyl)-1,7,8,9-tetrahydro-pyrano[2,3-g]indazol-8-ol;
(R)-1-((S)-2-Aminopropyl)-1,7,8,9-tetrahydro-pyrano[2,3-g]indazol-8-ol;
(S)-1-((S)-2-Aminopropyl)-1,7,8,9-tetrahydro-pyrano[2,3-g]indazol-8-ol;
1-((S)-2-Aminopropyl)-3-methyl-1,7,8,9-tetrahydro-pyrano[2,3-g]indazol-8-ol;
1-(S)-1-Pyrrolidin-2-ylmethyl-1,7,8,9-tetrahydro-pyrano[2,3-g]indazol-8-ol;
1-((S)-2-Aminopropyl)-5-fluoro-1,7,8,9-tetrahydro-pyrano[2,3-g]indazol-8-ol;
(R)-1-((S)-2-Aminopropyl)-1,7,8,9-tetrahydro-pyrano[2,3-g]indazol-8-ylamine;
[1-((S)-2-Aminopropyl)-1,7,8,9-tetrahydro-pyrano[2,3-g]indazol-8-yl]-dimethylamine;
[1-((S)-2-Aminopropyl)-1,7,8,9-tetrahydro-pyrano[2,3-g]indazol-8-yl]-methanol;
1-((S)-2-Aminopropyl)-1,7,8,9-tetrahydro-pyrano[2,3-g]indazole-8,9-diol;
1-((S)-2-Aminopropyl)-9-methoxy-1,7,8,9-tetrahydro-pyrano[2,3-g]indazol-8-ol;
1-(2-Aminopropyl)-3,7,8,9-tetrahydro-pyrano[3,2-e]indazol-8-ol;
1-(Pyrrolidin-2-ylmethyl)-3,7,8,9-tetrahydro-pyrano[3,2-e]indazol-8-ol; is 1-((S)-2-Aminopropyl)-3,7,8,9-tetrahydro-pyrano[3,2-e]indazol-8-ol;
1-((S)-2-Aminopropyl)-3-methyl-3,7,8,9-tetrahydro-pyrano[3,2-e]indazol-8-ol;
N-[2-[(R)-1-((S)-2-amino-propyl)-1,7,8,9-tetrahydro-pyrano[2,3-g]indazol-8-yloxy]ethyl]-acetamide;
2-[(R)-1-((S)-2-amino-propyl)-1,7,8,9-tetrahydro-pyrano[2,3-g]indazol-8-yloxy]-ethanol;
2-[(R)-1-((S)-2-amino-propyl)-1,7,8,9-tetrahydro-pyrano[2,3-g] indazol-8-yloxy]-acetamide;
[(R)-1-((S)-2-amino-propyl)-1,7,8,9-tetrahydro-pyrano[2,3-g]indazol-8-yloxy]-acetic acid tert-butyl ester;
N-[2-[(R)-1-((S)-2-Aminopropyl)-1,7,8,9-tetrahydropyrano[2,3-g]indazol-8-yloxy]-ethyl]acetamide;
2-[(R)-1-((S)-2-Aminopropyl)-1,7,8,9-tetrahydro-pyrano[2,3-g]indazol-8-yloxy]-ethanol;
(S)-2-[(R)-8-(2-Methoxyethoxy)-8,9-dihydro-7H-pyrano[2,3-g]indazol-1-yl]-1-methylethylamine;
2-[(R)-1-((S)-2-Aminopropyl)-1,7,8,9-tetrahydro-pyrano[2,3-g]indazol-8-yloxy]-acetamide;
2-[(R)-1-((S)-2-Aminopropyl)-1,7,8,9-tetrahydro-pyrano[2,3-g]indazol-8-yloxy]-N-hydroxy-acetamide;
1-[(R)-1-((S)-2-Aminopropyl)-1,7,8,9-tetrahydro-pyrano[2,3-g]indazol-8-yl]-3-ethyl-1-methylurea;
(S)-1-Methyl-2-(3,7,8,9-tetrahydro-pyrano[3,2-e]indazol-1-yl)-ethylamine;
2-[(R)-1-((S)-2-Aminopropyl)-3,7,8,9-tetrahydro-pyrano[3,2-e]indazol-8-yloxy]-ethanol;
[1-((S)-2-Aminopropyl)-7,8-dihydro-1H-furo[2,3-g]indazol-7-yl]-methanol;
2-[(S)-1-((S)-2-Aminopropyl)-7,8-dihydro-3H-furo[3,2-e]indazol-7-yl]-acetamide; or combinations thereof.
Certain compounds of Formula I can contain one or more chiral centers. The present invention contemplates all enantiomers, diastereomers, and mixtures thereof.
In the above definitions, the total number of carbon atoms in a substituent group is indicated by the Ci-j prefix where the numbers i and j define the number of carbon atoms. This definition includes straight chain, branched chain, and cyclic alkyl or (cyclic alkyl)alkyl groups. A substituent may be present either singly or multiply when incorporated into the indicated structural unit. For example, the substituent halogen, which means fluorine, chlorine, bromine, or iodine, would indicate that the unit to which it is attached may be substituted with one or more halogen atoms, which may be the same or different.
The compounds of Formula I can be prepared by using one of several synthetic procedures. For example, 1-(2-aminopropyl)-1,7,8,9-tetrahydro-pyrano[2,3-g]indazol-8-ols can be prepared from an appropriately protected 1-(6-hydroxyindazol-1-yl)-propan-2-ol 1 as outlined in Scheme 1. Pg denotes a suitable protective group to assure that a particular atom is not modified during the indicated chemical reaction. 
Other compounds of Formula I can be prepared from 12 through selected functional group transformations well known in the art. For example, initial protection of the primary amine group followed by activation of the hydroxyl group by formation of a sulfonate ester, e.g. methanesulfonyl, and subsequent reaction with a desired nucleophile such as alkylamines, dialkylamines, aryl or alkylthiols, and the like, will provide compounds 14 of Formula I. Furthermore, direct oxidation of 13 with a suitable oxidizing agent, for example, a hypervalent iodine reagent, such as o-iodoxybenzoic acid [J. Org. Chem. 60, 7272 (1995)], provides the ketone 16, which can be functionalized to provide yet other compounds of Formula I, such as 17, via reductive alkylation, and 15, via Grignard addition. 
Alternately, compounds of Formula I can be prepared from appropriately substituted 5-propargyloxy-indazoles (19) via initial Claisen rearrangement reactions [Tetrahedron Lett. 33, 2179 (1992), ibid. 35, 45 (1994), ibid. 41, 3541 (2000)] to give the intermediate substituted pyrano[2,3-g]indazoles 20 (Scheme 3). Further synthetic manipulation of 20, for example, as outlined in Schemes 3-5, using well-known functional group transformations provides yet other desirable compounds of Formula I. 
The 1-(hydroxyalkyl)-indazoles of interest for the preparation of compounds of Formula I can be prepared as outlined in Scheme 6 and in co-pending U.S. Patent Application No. 60/295,427, incorporated in its entirety by reference herein. Reaction of the activated fluorophenol 30 with the appropriate amino alcohol 31, which, when A is nitrile, is reduced to provide the corresponding aldehyde 32. Nitrosation to provide 33 followed by reductive cyclization provides the 1-(hydroxyalkyl)-indazoles 34. 
Intermediate pyranoindazoles 34 can also be prepared by alkylation of the appropriate O-protected 6-hydroxy-indazole (35), where suitable O-protective groups are e.g. methyl or benzyl, by methods well known in the art and described in Scheme 7 [U.S. Pat. No. 5,494,928 (1997), WO98/30548 (1998)], with the desired epoxide, e.g. propylene oxide Alternately, it can be advantageous for the preparation of certain compounds to alkylate 35 using chloroacetone followed by reduction, e.g. with NaBH4, of the intermediate ketone to obtain the intermediate 34. 
It can be advantageous to prepare certain compounds of Formula I from a suitably substituted 1,7,8,9-tetrahydro-pyrano[2,3-g]indazole, such as 36 as outlined in Scheme 8. For example, alkylation of 36 according to the conditions described for Scheme 4 above, followed by suitable activation of the hydroxyl group toward subsequent nucleophilic amination by formation of a sulfonate ester [J. Chem. Soc., Perkins Vol. 1:1479, 1981], e.g. methanesulfonyl, toluenesulfonyl, bromophenylsulfonyl, or nitrophenylsulfonyl, and reaction with the desired amine provides compounds 38 of Formula I. 
Furthermore, reaction of indazoles 36 with the activated alaminol 39 provides 40, which following deprotection gives compounds 38 of Formula I as shown in Scheme 9. Replacement of 39 in Scheme 9 with, for example, an activated sulfonate ester, or the corresponding halide, or N-protected (e.g. with t-butyloxycarbonyl, benzyloxycarbonyl) pyrrolidin-3-methanol would, following removal of the amine protective group, provide yet another compound of Formula I. Further, replacement of 39 in Scheme 9 with an activated sulfonate ester of N-(2-hydroxy-1,1-dimethyl-ethyl)-phthalimide [J. Amer. Chem. Soc., Vol. 108:3811, 1986], 2-[(t-butyloxycarbonyl)amino]-2-methylpropanol [J. Amer. Chem. Soc. Vol. 113:8879, 1991], 1-[(t-butyloxycarbonyl)amino]-cyclopropyl-1-is methanol [J. Med. Chem., Vol. 31:1694, 1988], or 2-methyl-2-nitro-propan-1-ol [J. Amer. Chem. Soc., Vol. 68:12, 1946] would, following removal of the N-protective groups in the first three cases, or reduction of the nitro group in the latter, provide yet other examples 38 of Formula I. 
Certain desirable substituted 1,7,8,9-tetrahydro-pyrano[2,3-g]indazoles can be prepared from the appropriately substituted 1H-indazol-6-ol (41), as described in the synthetic sequence outlined in Scheme 10. Alkylation of indazoles 41 with allyliodide followed by treatment under Claisen rearrangement conditions provides 43. Protection of the hydroxyl group from further reaction by conversion to, for example an ester such as acetyl, and similar incorporation of a protective group on the nitrogen atom, for example by reaction with a suitable isocyanide to give a ureide, provides the desired allyl indazole 45. Epoxidation of the olefin with, for example 3-chloro-perbenzoic acid, and subsequent cyclization under basic conditions, provides the pyranoindazole intermediate 47. Conversion of the hydroxyl group of pyranoindazole 47 into yet other functional groups consistent with Formula I can be accomplished by the application of functional group transformations well known in the art. 
The desired pyrano[3,2-e]indazol-3-ethylamines, such as 49, 51 and 52 (Scheme 11) of Formula I can be prepared from the appropriately substituted 3-(2-hydroxypropyl)-1H-indazol-5-ol 48 by the methods described in Schemes 1-5 and as described in International Patent Application No. PCT/US00/31143, incorporated in its entirety by reference herein. 
Certain desirable substituted 7,8-dihydro-furano[2,3-g]indazoles of Formula I can be prepared from the appropriately substituted 1H-indazol-6-ol (53), as described in the synthetic sequence outlined in Scheme 12. Additionally, the application of standard functional group transformations well known to the art, for example by modification of compound 60, can give yet other compounds of Formula I. 
Using the procedures described in Schemes 1-12 (above), the Examples 1-19 (below), and well known procedures, one skilled in the art can prepare the compounds disclosed herein. Preferred compounds according to the present invention are those set forth in Tables 1-3, below. In Tables 1-3, the following abbreviations correspond to the indicated structural elements: Me is methyl; Et is ethyl; Pr is propyl; iBu is isobutyl; Ac is acetyl.
The compounds of the present invention can be used to lower and control IOP including IOP associated with normotension glaucoma, ocular hypertension, and glaucoma in warm blooded animals including humans. Since the treatment of glaucoma is preferably with compounds that do not enter the CNS, relatively polar compounds that are 5-HT2 agonists are of particular interest. The compounds are preferably formulated in pharmaceutical compositions which are preferably suitable for topical delivery to the eye of the patient.
The compounds of this invention, Formula I, can be incorporated into various types of pharmaceutical compositions, such as ophthalmic formulations for delivery to the eye (e.g., topically, intracamerally, or via an implant). The compounds are preferably incorporated into topical ophthalmic formulations for delivery to the eye. The compounds may be combined with ophthalmologically acceptable preservatives, viscosity enhancers, penetration enhancers, buffers, sodium chloride, and water to form an aqueous, sterile ophthalmic suspension or solution. Ophthalmic solution formulations may be prepared by is dissolving a compound in a physiologically acceptable isotonic aqueous buffer. Further, the ophthalmic solution may include an ophthalmologically acceptable surfactant to assist in dissolving the compound. Furthermore, the ophthalmic solution may contain an agent to increase viscosity, such as hydroxymethylcellulose, hydroxyethylcellulose, hydroxypropylmethylcellulose, methylcellulose, polyvinylpyrrolidone, or the like, to improve the retention of the formulation in the conjunctival sac. Gelling agents can also be used, including, but not limited to, gellan and xanthan gum. In order to prepare sterile ophthalmic ointment formulations, the active ingredient is combined with a preservative in an appropriate vehicle, such as, mineral oil, liquid lanolin, or white petrolatum. Sterile ophthalmic gel formulations may be prepared by suspending the active ingredient in a hydrophilic base prepared from the combination of, for example, carbopol-974, or the like, according to the published formulations for analogous ophthalmic preparations; preservatives and tonicity agents can be incorporated.
The compounds are preferably formulated as topical ophthalmic suspensions or solutions, with a pH of about 5 to 8. The compounds will normally be contained in these formulations in an amount 0.01% to 5% by weight, but preferably in an amount of 0.25% to 2% by weight. Thus, for topical presentation 1 to 2 drops of these formulations would be delivered to the surface of the eye 1 to 4 times per day according to the discretion of a skilled clinician.
The compounds can also be used in combination with other agents for treating glaucoma, such as, but not limited to, xcex2-blockers (e.g., timolol, betaxolol, levobetaxolol, carteolol, levobunolol, propranolol), carbonic anhydrase inhibitors (e.g., brinzolamide and dorzolamide), xcex11 antagonists (e.g., nipradolol), xcex12 agonists (e.g. iopidine and brimonidine), miotics (e.g., pilocarpine and epinephrine), prostaglandin analogs (e.g., latanoprost, travaprost, unoprostone, and compounds set forth in U.S. Pat. Nos. 5,889,052; 5,296,504; 5,422,368; and 5,151,444, xe2x80x9chypotensive lipidsxe2x80x9d (e.g., lumigan and compounds set forth in U.S. Pat. No. 5,352,708), and neuroprotectants (e.g., compounds from U.S. Pat. No. 4,690,931, particularly eliprodil and R-eliprodil, as set forth in a pending application U.S. Ser. No. 06/203,350, and appropriate compounds from WO 94/13275, including memantine.
In the formulas described above, the alkyl group can be straight-chain, branched or cyclic and the like. Halogen includes Cl, Br, F, or I. Alkoxy is understood as an alkyl group bonded through an oxygen atom.
The compounds of the present invention preferably function as 5-HT2 agonists and preferably do not enter the CNS. Compounds having the ability to be a 5-HT2 agonist are beneficial for controlling IOP as well as the treatment of glaucoma as shown in International Published Patent Application No. WO 00/16761, incorporated in its entirety by reference herein.
The compounds of the present invention preferably provide increased chemical stability and preferably achieve the desired level of therapeutic activity which includes a lowering or controlling of IOP.
The compounds of the present invention can be used in controlling or lowering IOP in warm blooded animals including humans. Preferably, an effective amount of the compound is administered to the patient such that the IOP is controlled or lowered to acceptable levels. Furthermore, the compounds of the present invention can be used to treat glaucoma in warm blooded animals, including humans, by administering an effective amount of the compound to a patient in need of such treatment to treat the glaucoma. Examples of suitable pharmaceutical acceptable amounts of the compounds of the present invention include those amounts shown in the Examples.
Another embodiment of the present invention is a method to block or bind to serotonin receptors comprising administering an effective amount of at least one compound of the present invention to a patient using an amount effective to block or bind to serotonin receptors, such as, but not limited to, the dosage levels described herein.
The following examples are given to illustrate the preparation of compounds that are the subject of this invention but should not be construed as implying any limitations to the claims. The preferred compounds of Formula I are described in Examples 4, 5 and 13. The most preferred compound is Example 4. The proton magnetic resonance spectrum of each compound of the Examples was consistent with the assigned structure.
To determine the affinities of serotonergic compounds at the 5-HT2 receptors, their ability to compete for the binding of the agonist radioligand [125I]DOI to brain 5-HT2 receptors is determined as described below with minor modification of the literature procedure [Neuropharmacology, 26, 1803 (1987)]. Aliquots of post mortem rat or human cerebral cortex homogenates (400 xcexcL) dispersed in 50 mM Tris HCl buffer (pH 7.4) are incubated with [125I]DOI (80 pM final) in the absence or presence of methiothepin (10 xcexcM final) to define total and non-specific binding, respectively, in a total volume of 0.5 mL. The assay mixture is incubated for 1 hour at 23xc2x0 C. in polypropylene tubes and the assays terminated by rapid vacuum filtration over Whatman GF/B glass fiber filters previously soaked in 0.3% polyethyleneimine using ice-cold buffer. Test compounds (at different concentrations) are substituted for methiothepin. Filter-bound radioactivity is determined by scintillation spectrometry on a beta counter. The data are analyzed using a non-linear, iterative curve-fitting computer program [Trends Pharmacol. Sci., 16, 413 (1995)] to determine the compound affinity parameter. The concentration of the compound needed to inhibit the [125I]DOI binding by 50% of the maximum is termed the IC50 or Ki value.
The receptor-mediated mobilization on intracellular calcium ([Ca2+]i) was studied using the Fluorescence Imaging Plate Reader (FLIPR) instrument. Rat vascular smooth muscle cells, A7r5, were grown in a normal media of DMEM/10% FBS and 10 xcexcg/mL gentamycin. Confluent cell monolayers were trypsinized, pelleted, and re-suspended in normal media. Cells were seeded in a 50 xcexcL volume at a density of 20,000 cells/well in a black wall, 96-well tissue culture plate and grown for 2 days.
On the day of the experiment, one vial of FLIPR Calcium Assay Kit dye was re-suspended in 50 mL of a FLIPR buffer consisting of Hank""s Balanced Salt Solution (HBSS), 20 mM HEPES, and 2.5 mM probenecid, pH 7.4. Cells were loaded with the calcium-sensitive dye by addition of an equal volume (50 xcexcL) to each well of the 96-well plate and incubated with dye for 1 h at 23xc2x0 C.
Typically, test compounds were stored at 25 xcexcM in 50% DMSO/50% Ethanol solvent. Compounds were diluted 1:50 in 20% DMSO/20% Ethanol. For xe2x80x9chitxe2x80x9d screening, compounds were further diluted 1:10 in FLIPR buffer and tested at a final concentration of 10 xcexcM. For dose-response experiments, compounds were diluted 1:50 in FLIPR buffer and serially diluted 1:10 to give a 5- or 8-point dose-response curve.
The compound plate and cell plate were placed in the FLIPR instrument. At the beginning of an experimental run, a signal test was performed to check the basal fluorescence signal from the dye-loaded cells and the uniformity of the signal across the plate. The basal fluorescence was adjusted between 8000-12000 counts by modifying the exposure time, the camera F-stop, or the laser power. Instrument settings for a typical assay were the following: laser power 0.3-0.6 W, camera F-stop F/2, and exposure time 0.4 sec. An aliquot (25 xcexcL) of the test compound was added to the existing 100 xcexcL dye-loaded cells at a dispensing speed of 50 xcexcL/sec. Fluorescence data were collected in real-time at 1.0 sec intervals for the first 60 secs and at 6.0 sec intervals for an additional 120 secs. Responses were measured as peak fluorescence intensity minus basal and where appropriate were expressed as a percentage of a maximum 5-HT-induced response. When the compounds were tested as antagonists against 10 xcexcM 5-HT, they were incubated with the cells for 15 minutes prior to the addition of 5-HT.
The above procedures were used to generate the data shown in Table 4.
Step A: 6-Allyloxy-1H-indazole
To a solution of 1H-indazol-6-ol (20.0 g, 150 mmol) in acetone (450 mL) was added pulverized potassium carbonate (22.4 g, 162 mmol), cesium carbonate (2.00 g, 5.7 mmol), and allyl iodide (14.63 mL, 160 mmol) and the mixture was stirred for 18 h at ambient temperature. Additional potassium carbonate (5.00 g, 36 mmol) and allyl iodide (1.4 mL, 15 mmol) were added and the mixture was stirred for 2 h followed filtration. Water (200 mL) was added to the filtrate and the volume of the mixture was reduced by about half in vacuo and extracted with dichloromethane (2xc3x97100 mL). The combined extracts were dried (MgSO4) and evaporated to a residue which was purified by chromatography (silica, 20% to 50% EtOAc/hexane) to give a yellow solid (14.7 g, 56%): mp 110-112xc2x0 C.; LC/MS (+APCI) m/z 175 (M+H). Unreacted starting material was recovered (4.71 g).
Step B: 7-Allyl-1H-indazol-6-ol
A solution of the product from Step A (14.2 g, 82 mmol) in 1,2-dichlorobenzene (90 mL) was fluxed for 6 h and the reaction mixture was evaporated to a residue which was purified by chromatography (silica, EtOAc) to give a tan solid (8.59 g, 60%) that was used in the next step: LC/MS (+APCI) m/z 175 (M+H).
Step C: Acetic Acid 7-allyl-1H-indazol-6-yl Ester
A solution of the product from Step B (6.35 g, 37 mmol) in THF (100 mL) containing triethylamine (7.6 ml, 55 mmol) was stirred for 5 minutes at ambient temperature, cooled to 0xc2x0 C. (ice bath), and acetyl chloride (2.63 mL, 37 mmol) was added. The mixture was stirred at 0xc2x0 C. for 2 hours, additional acetyl chloride (0.26 mL, 3.7 mmol) was added, and the mixture stirred for 10 min at which point another portion of acetyl chloride (0.26 ml, 3.7 mmol) was added and stirring continued for 15 min. The reaction was quenched with triethyl amine (1 mL) and saturated aqueous sodium bicarbonate (100 mL) and extracted with ethyl acetate (100 mL). The extract was dried (MgSO4) and evaporated to an oil (9.27 g) which was purified by chromatography (silica, 10% to 50% EtOAc/hexane) to give a white solid, (3.50 g, 44%): LC/MS (+APCI) m/z 217 (M+H).
Step D: Acetic Acid 7-allyl-1-ethylcarbamoyl-1H-indazol-6-yl Ester
To a solution of the product from Step C (2.5 g, 11.6 mmol) in THF (10 mL) was added ethylisocyanate (1.01 ml, 13 mmol) and the mixture heated at 70xc2x0 C. for 18 h. The reaction mixture was evaporated to a residue which was purified by chromatography (silica, 10% to 50% EtOAc/hexane) to give a colorless oil (2.70 g, 81%): LC/MS (+APCI) m/z 288 (M+H).
Step E: Acetic Acid 1-ethylcarbamoyl-7-oxiranylmethyl-1H-indazol-6-yl Ester
To a solution of the product from Step D (2.70 g, 9.4 mmol) in dichloromethane (15 mL) was added 3-chloro-perbenzoic acid (2.31 g, 10.3 mmol, 77% pure) and the mixture stirred at ambient temperature for 1 h. Additional 3-chloro-perbenzoic (0.2 g, 0.9 mmol) was added and the reaction continued for 3 h. The reaction was quenched with saturated aqueous sodium bicarbonate (100 mL) and extracted with dichloromethane (50 mL). The extract was dried (MgSO4) and evaporated to a white solid (1.59 g, 56%): mp 110-111xc2x0 C.; LC/MS (+APCI) m/z 304 (M+H).
Step F: 1,7,8,9-Tetrahydro-pyrano[2,3-g]indazol-8-ol
To a solution of the product of Step E (1.44 g, 4.75 mmol) in methanol (100 mL) was added saturated aqueous potassium carbonate (10 mL) and the mixture stirred for 18 h at ambient temperature. Water (200 mL) was added to the reaction mixture and the pH adjusted to 7 with conc HCl followed by extraction ethyl acetate (5xc3x97100 mL). The combined extracts were dried (MgSO4) and evaporated to tan solid (0.84 g, 93%): 1H NMR (DMSO-d6) xcex4 12.77 (s, 1H), 7.94 (s, 1H), 7.49 (d, J=6.0 Hz, 1H), 6.66 (d, J=6.0 Hz, 1H), 5.02 (t, J=6.0 Hz, 1H), 4.85-4.95 (m, 1H), 3.62 (m, 2H), 2,9-3.4 (m, 2H); LC/MS (+APCI) m/z 191 (M+H).
Step A: (6-Benzyloxy-indol-1-yl)-propan-2-ol
To a stirred, cooled (10xc2x0 C.) suspension of sodium hydride (80.7 g of a 60% dispersion to in mineral oil, 2.02 mol) in anhydrous THF (1.9 L) was added a solution of 6-benzyloxyindole (375 g, 1.68 mol) in anhydrous THF (1.9 L) keeping the temperature below 25xc2x0 C. After 2 h at 10xc2x0 C., propylene oxide (140 mL, 2.0 mol) was added dropwise keeping the temperature below 25xc2x0 C. After 48 h at 10xc2x0 C., propylene oxide (71 mL, 1.0 mol) was added. After 96 h at 10xc2x0 C., saturated aqueous potassium dihydrogenphosphate (3.8 L) and ethyl acetate (3.8 L) were carefully added, the layers were separated and the aqueous solution was extracted with 3.8 L of ethyl acetate. The combined organic extracts were dried over sodium sulfate and concentrated in vacuo to yield a solid (520 g, 110%, contains mineral oil).
Step B: N-(5-Benzyloxy-2-formylphenyl)-N-(2-hydroxypropyl)-formamide
A solution of the product from Step A (172 g) in 1.5 L of dichloromethane was cooled to xe2x88x9278xc2x0 C. and ozonized (4% ozone in oxygen). Excess ozone was displaced with oxygen for 5 min, followed by addition of dimethyl sulfide (78 mL) and warming to 25xc2x0 C. The solution was concentrated to half volume, eluted through Florisil rinsing with ethyl ether-ethyl acetate and concentrated in vacuo. This procedure was repeated four times: one 172 g batch and three 58 g batches. The combined products were passed through silica (2.5 kg) with a gradient of 10%-80% ethyl acetate-hexane to yield, after concentration in vacuo, an oil (351 g, 70%).
Step C: 4-Benzyloxy-2-(2-hydroxy-propylamino)benzaldehyde
An ice-cooled solution of the product from Step B (298 g, 0.95 mol) in THF (3 L) was treated with 1 M aqueous sodium hydroxide (1.95 L, 1.9 mol) keeping the temperature below 8xc2x0 C. After the starting material was consumed, the mixture was diluted with brine and extracted twice with ethyl ether. The organic solution was washed with water until neutral and then with brine, dried over sodium sulfate, treated with charcoal and passed through silica (1 kg) with ether and with 1:1 ethyl acetate-hexane to yield, after concentration in vacuo, a yellow solid (207 g, 76%).
Step D: 1-(6-benzyloxy-indazol-1-yl)-propan-2-ol
The product of Step C (202.7 g, 0.71 mol) was treated as described for Steps C and D of Preparation 3. After the nitrosamine intermediate had been converted to a mixture of the desired indazole product and unreacted starting material (5:1), sodium nitrite (29.5 g, 0.43 mol) was added to renitrosate the starting material. Zinc dust (84 g, 1.28 mol) was then added in portions with cooling as described. When the starting material was consumed, the reaction mixture was worked up as described and combined with the product from another batch that started with 176 g of the product of Step C. The combined crude products were purified by chromatography (Biotage Kiloprep-250) to give a solid (226 g, 60%): 99% purity by HPLC.
Step A: 4-Benzyloxy-2-fluorobenzonitrile
Benzyl bromide (467 mL, 3.93 mol) and potassium carbonate (1.4 kg, 10.1 mol) were added to a solution of 2-fluoro-4-hydroxybenzonitrile (490 g, 3.57 mol) in acetone (3.4 L). The stirred mixture was heated at 60xc2x0 C. for 20 h, then cooled and filtered. The filtrate was concentrated and the resulting solid was triturated with 10% ethyl acetate-hexane (5 L) and vacuum dried at 35xc2x0 C. to give the desired product (787 g, 97%).
Step B: 4-Benzyloxy-2-((R)-2-hydroxy-propylamino)benzonitrile
A solution of (R)-(xe2x88x92)-1-amino-propan-2-ol (389 g, 5.19 mol) in dimethyl sulfoxide (600 mL) was added to a solution of the product from Step A (786 g, 3.46 mol), basic alumina (786 g), and 4A molecular sieves (131 g). The stirred mixture was heated at 110-140xc2x0 C. for 24 h, cooled and filtered, the filter-aide was washed with 10 L of 4:1 ether-ethyl acetate followed by 4 L of 3:2 ethyl acetate-hexane. The organic washes were extracted with water (5 L) and the aqueous phase was extracted with 25% ethyl acetate-hexane (4xc3x972 L). The combined organic phases were washed with water and brine, dried over sodium sulfate, concentrated to about 3 L and allowed to stand for 48 h. The precipitated solid was collected by filtration, washed with hexane, and vacuum-dried to provide the desired product in two crops (619 g and 86 g). The concentated supernatant was applied to a 5 kg silica gel pad and eluted with a gradient of 10-50% ethyl acetate-hexane to give, after concentration in vacuo, additional product (119 g): total yield was 791 g (81%).
Step C: 4-Benzyloxy-2-((R)-2-hydroxy-propylamino)benzaldehyde
Sodium hypophosphite hydrate (986 g, 11.2 mol) and Raney nickel (500 g of a 50% aqueous suspension) were added to a solution of the product from Step B (790 g, 2.8 mol) in a 2:1:1 mixture of pyridine-acetic acid-water (7 L). The mixture was stirred at 45xc2x0 C. for 7 h, then cooled to 25xc2x0 C. overnight and filtered through a filter-aide rinsing with water and ethyl acetate. The filtrate was washed with saturated sodium hydrogenphosphate to pH 5, water and brine, dried over sodium sulfate and concentrated. During concentration, 4 L of heptane was added to azeotropically remove pyridine. After 8 L of solvent had been removed the product solidified. Heptane (5 L) was added and the solid was triturated, isolated by filtration and vacuum dried at 35xc2x0 C. to yield the desired product (722 g, 90%).
Step D: (R)-1-(6-benzyloxy-indazol-1-yl)-propan-2-ol
Sodium nitrite (209 g, 3.03 mol) was added over 25 min to a stirred solution of the product from Step C (720 g, 0.2.53 mol) in acetic acid (5.6 L) and water (1.4 L), keeping the temperature below 25xc2x0 C. The resulting solution of the nitrosamine intermediate was cooled in an ice bath, and zinc dust (595 g, 9.10 mol) was added in 25 g portions over 3.5 h, keeping the temperature below 35xc2x0 C. Ethyl acetate (7 L) was added and the thick suspension was filtered through a sintered glass funnel, washing with ethyl acetate (7.5 L). To the filtrate containing a 5:1 mixture of the desired indazole product and regenerated starting material was added Girard""s Reagent T (98 g, 0.58 mol). After stirring at 25xc2x0 C. for 1 day, another 150 g (0.90 mol) of Girard""s Reagent T was added. After 3 more days all of the starting material was consumed. The mixture was extracted twice with water, with aqueous sodium hydrogenphosphate to remove acetic acid, water and brine, dried over sodium sulfate, filtered through Florisil, and concentrated. The residue was passed through 5 kg of silica with 1:1 ethyl acetate-hexane. Appropriate fractions were combined and concentrated, and heptane (4 L) was added to precipitate the indazole product. The solid was collected by filtration, washed with 1:1 ethyl acetate-hexane and vacuum dried at 35xc2x0 C. give a yellow solid (417 g, 58%): HPLC analysis: (R)-96.7%; (S)-0.3%; starting material 3%. Concentration of the supernatant afforded an additional 141 g (20%) of the desired product.
Method 1. This S stereoisomer was prepared as described above for the preparation of racemic 1-(6-benzyloxyindazol-1-yl)-propan-2-ol, but using (S)-1-amino-2-propanol instead of the racemic aminoalcohol.
Method 2. Step A: 4-Benzyloxy-2-fluoro-benzonitrile
A mixture of 2-fluoro-4-hydroxybenzonitrile (15.0 g, 109 mmol), potassium carbonate (21.0 g, 152 mmol), and benzyl bromide (19.6 g, 115 mmol) in acetone (150 mL) under nitrogen was heated at 50xc2x0 C. overnight. The solid was removed by filtration and the filtrate evaporated to a residue that was mixed with ethyl acetate (500 mL). This solution was washed with brine, dried, and evaporated to give an amorphous solid: (24.9 g, 100%).
Step B: 4-Benzyloxy-2-((S)-2-hydroxy-propylamino)-benzonitrile
A mixture of the product from Step A (24.8 g, 109 mmol), (S)-1-amino-2-propanol (12.3 g, 164 mmol), 4A molecular sieves (4.0 g), and basic alumina (32 g) in anhydrous dimethyl sulfoxide (100 mL) under nitrogen was heated at 95xc2x0 C. for 40 h. The suspension was cooled to ambient temperature, filtered through a filter-aide that was washed with ethyl acetate (2xc3x97300 mL) and water (300 mL). The aqueous layer of the filtrate was extracted with ethyl acetate (2xc3x97300 mL) and the combined organics were washed with brine (200 mL), dried (MgSO4), and purified by chromatography (silica, EtOAc/hexane) to give a viscous oil (24.9 g, 81%).
Step C: 4-Benzyloxy-2-((S)-2-hydroxy-propylamino)-benzaldehyde
To a solution of the product of Step B (19.3 g, 68.3 mmol) in a mixture of anhydrous cyclohexane and THF (200 mL, 40 mL) at 0xc2x0 C. under nitrogen was added diisobutylammonium hydride (1 M solution in hexane, 239 mL, 239 mmol) over 30 min. This mixture was stirred 18 h at ambient temperature, additional diisobutylammonium hydride (40 mL, 40 mmol) was added, and the mixture was stirred an additional 24 h. The reaction mixture was cooled on an ice bath and the reaction was quenched by the addition of MeOH (exothermic) and 2 N HCl to maintain a pH of 1. The mixture was extracted with EtOAc (3xc3x97300 mL) and the extracts were dried and concentrated to a brown oil (18.5 g). The crude oil was triturated with EtOAc/hexane, and filtered to give an oil (16.1 g, 83% crude yield). A small portion of this material was purified by chromatography (silica, 20% to 50% EtOAc/hexane) to afford a solid; mp 68-69xc2x0 C.
Step D: (S)-1-(6-Benzyloxyindazol-1-yl)-propan-2-ol (4)
To a mixture of the product from Step C (16.0 g, 56.1 mmol) in acetic acid/water (150 mL/30 mL) at 0xc2x0 C. was added sodium nitrite (7.75 g, 112 mmol) in portions over 40 min. The mixture was stirred for 50 min, cooled (ice bath), and zinc (14.7 g, 224 mmol) was added in portions. After 1 h the suspension was warmed to room temperature and more zinc was added (14.7 g, 224 mmol). The mixture was stirred for 1 h, concentrated, and extracted with EtOAc (2xc3x97300 mL). The extracts were filtered through a filter-aide, and the filtrate was washed with saturated aqueous disodium hydrogen phosphate (to pH 8) and brine, dried, and purifed by chromatrography (silica, 25% EtOAc/hexane) to afford an oil (7.01 g, 44%).
Step A: N-(4-Methoxy-2-methyl-phenyl)-2,2-dimethyl-propionamide
To a stirred mixture of 4-methoxy-2-methylphenylamine (15.0 g, 109 mmol) and triethylamine (13.3 g, 131 mmol) in anhydrous THF (350 mL) at 0xc2x0 C. was added pivaloyl chloride (14.1 mL, 13.8 g, 114 mmol). A white precipitate formed and the suspension was stirred for additional 30 min before water (10 mL) was added. The mixture was stirred for 30 min, THF evaporated and the residue was mixed with a saturated aqueous sodium bicarbonate solution and extracted with ethyl acetate. The combined extracts were dried (MgSO4), filtered and evaporated to an oil (23.5 g, 97%): LC/MS (+APCI) m/z 222 (M+H).
Step B: N-[2-(3-Hydroxybutyl)-4-methoxyphenyl]-2,2-dimethylpropionamide
To a stirred solution of the the product from Step A (3.00 g, 13.6 mmol) at 0xc2x0 C. in anhydrous THF (50 mL) was added a solution of 2.5 M n-BuLi in hexanes (13.6 mL, 2.5 equiv.) over about 2 min under a nitrogen atmosphere. After 10 minutes a solution of (R)-propylene oxide (1.18 g, 1.5 eq) in anhydrous THF (5 mL) was added and the mixture was stirred for about 30 min. The reaction was quenched by the addition of ice-water. The THF was evaporated and the residue was extracted with ethyl acetate to give a viscous oil (4.03 g), which was used in next reaction without further purification: LC/MS (+APCI) m/z 280 (M+H).
Step C: (R)-2-(3-Hydroxybutyl)-4-methoxyphenylammonium Chloride
A mixture of the the product from Step B (7.31 g, 2.29 mmol), ethanol (100 mL), concentrated HCl (50 mL) and water (30 mL) was heated at reflux for three days. The volatile material was removed by evaporation and the residue was dried overnight. The residue was triturated with ethyl acetate, filtered and dried under a vacuum to give an amorphous powder (4.11 g, 68%).
Step D: (R)-1-(5-Methoxy-1H-indazol-3-yl)-propan-2-ol
To a stirred suspension of the product from step C (2.66 g, 11.5 mmol) in dichloromethane (150 mL) at ambient temperature was added isoamyl nitrite (2.47 mL, 18.4 mmol, 1.6 equiv.). After 30 minutes tetrabutylammonium acetate (5.54 g, 18.4 mmol, 1.6 eq) was added and the mixture was stirred for 2 hours. Water was added to the mixture and the organic layer was separated and washed with 2 N NaOH and water. After drying and evaporation the crude product was purified by column chromatography (gradient of 20% to 40% ethyl acetate in hexane) to give an oil (1.58 g) that crystallized from ethyl acetate/hexane (1:1) to afford a solid (1.30 g, 55%): mp 89-91xc2x0 C.; LC/MS (+APCI) m/z 207 (M+H).